Reversing VTN Deficiency Inhibits the Progression of Pancreatic Cancer and Enhances Sensitivity to Anti-PD1 Immunotherapy

Siqi Zhao¹Zhaofeng Gao¹Lingyu Hu¹Yihan Li²Xiaoguang Wang¹Xiaoping Li¹Minjie Chen¹Fei Chen¹Zhengwei Song^1*

• ¹Jiaxing University, Jiaxing, China
• ²Nanjing Medical University, Nanjing, Jiangsu Province, China

Pancreatic cancer, one of the most lethal malignancies with limited therapeutic options, urgently requires novel prognostic biomarkers and therapeutic targets. While the extracellular matrix protein vitronectin (VTN) has been implicated in tumor progression, its role in pancreatic cancer and immunotherapy remains unexplored.Here, we integrated single-cell RNA sequencing, public databases (TCGA, TISIDB), and functional assays to reveal that VTN expression is significantly downregulated in pancreatic cancer tissues compared to normal tissues, with lower levels correlating with advanced disease stages and poor prognosis. In vitro experiments demonstrated that VTN knockdown enhanced pancreatic cancer cell proliferation, invasion, and migration, whereas VTN overexpression suppressed these processes. Mechanistically, VTN expression was associated with immune regulatory factors and predicted improved survival in patients receiving anti-PD1/PD-L1 therapy. Critically, in a mouse subcutaneous tumor model, VTN overexpression not only inhibited tumor growth but also synergized with anti-PD1 immunotherapy to amplify therapeutic efficacy. Our findings establish VTN as a dual-functional regulator of pancreatic cancer progression and immunotherapy sensitivity, highlighting its potential as both a prognostic biomarker and a therapeutic target to enhance anti-PD1 efficacy in this intractable malignancy.